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    1. 407 C to T VHL gene mutation

      A 32-year old man was consulted at the Polish VHL Registry as a member of a family with suspected von Hippel-Lindau disease (VHL). He presented with endolymphatic sac tumour (19Y; 21Y); cerebral hemangioblastoma (24Y; 26Y); and retinal capillary hemangioblastoma. He had a germline missense VHL mutation NM_000551.3:c.194C>T(S65L) which was also found in two of his children. Note that the paper describes this variant as c.407C>T since it uses an older reference sequence (Latif et al.). His family members had lesions consistent with VHL disease including multiple central nervous system tumours (probable hemangioblastomas), renal tumours (probable renal cell carcinomas), pancreatic tumours (probable cysts and neuroendocrine tumours), temporal bone tumours (probable ELST), and loss of sight because of retinal detachment (probably in the case of retinal hemangiomas).

    1. 194C>T Ser65Leu Germline mutation

      PatientID: 30

      KindredID: 30

      Case: Age, sex, ethnicity unknown

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T) AND L89P (c.266T>A)

      MultipleGeneVariants: Somatic, VHL, c.266T>A (p.Leu89Pro)

    2. 194C>T Ser65Leu Germline mutation

      Tissues embedded in paraffin blocks were collected from 203 cHAB patients operated in different Medical Centres in Poland. Eight of these harboured germline mutations in unrelated patients from distinct undiagnosed VHL families. Various variants were unverified as somatic or germline as they were detected in tumour but blood samples were not tested. Other phenotypes and demographic information is not known. Patient 30 was found with a germline p.Ser65Leu mutation in the VHL gene. This patient also had a somatic mutation (c.266T>C p.Leu89Pro) in the tumour.

    1. 6f557.6n16.6↑407 C/T+9.6

      PatientID: 6

      KindredID: 6

      Case: F, 55Y0M, Ethnicity Unknown

      DiseaseAssertion: Assumed VHL

      FamilyInfo: No details on family information.

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: N/A

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: c.407C>T

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: 0, https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 19

      KindredID: 6

      Case: F, Age unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Family #6 is large. The proband (patient 12) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: The proband's uncle's granddaughter (ie. the granddaughter of uncle 2), patient 19, was asymptomatic at the time of the study.

      CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma )

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    2. PatientID: 13

      KindredID: 6

      Case: F, Age unknown, Chinese

      DiseaseAssertion: Asymptomatic

      FamilyInfo: Family #6 is large. The proband (patient 12) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13/ her daughter (asymptomatic,) 14/ her mother (CNS hemangioblastoma at age 59,) 15/ her uncle 1 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18/ the son of her uncle 2 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19/ the granddaughter of her uncle 2 (asymptomatic), 20/ the second son of her uncle 2 (asymptomatic), 21/ her aunt (CNS hemangioblastoma and retinal angioma at 53,) and 22/ her uncle 3 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16/ son of her uncle 1 (CNS hemangioblastoma at 22) and 17/ her uncle 2 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51).

      CasePresentingHPOs: N/A

      CaseHPOFreeText: The proband's daughter, patient 13, was asymptomatic at the time of the study.

      CaseNotHPOs: HP:0009711; HP:0002666; HP:0010797; HP:0001737; HP:0001732; HP:0005584 (Retinal capillary hemangioma, Pheochromocytoma, Hemangioblastoma, Pancreatic cysts, Abnormality of the pancreas, Renal cell carcinoma )

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    1. Gene analysis performed at that time showed mutation in VHL gene in exon 1 TCG(Ser65)→TTG(Leu).

      A case report of a female patient with cereballar hemangioblastoma at 23Y and endolympathic sac tumour repeating at 23Y and 25Y revealed a mutation c.194C>T in the VHL gene. The mutation was found in both the hemangioblastoma and and the ELST, as well as in the patient's father, concluding germline origin. The patient's father had cerebellar hemangioblastoma at age 30, and bilateral renal cell carcinoma. He died at 43Y due complications from metatasized RCC. The patient's grandfather and uncle also had VHL-like multi-tumours, but genetic confirmation was not determined and symptoms were not specified. Cosegregation with disease and multiple affected family members may be supportive of PP1. Patients' phenotypes are highly specific to VHL disease (PP4).

    2. Case 1: Clinical historyA 25-year-old woman presented with a 1-year history of slowly progressive and gradual decrease in hearing. Two years previously, the patient had undergone brain surgery because of hemangioblastoma of the cerebellum. Gene analysis performed at that time showed mutation in VHL gene in exon 1 TCG(Ser65)→TTG(Leu). On physical examination, she was found to have a middle ear mass that protruded into the external auditory canal. Bone destruction was found radiographically. At surgery, vascular tumor tissue and cysts were seen permeating and destroying the adjacent petrous portion of the temporal bone with invasion of the mastoid and the semicircular canal. The patient underwent a complete removal of the tumor from the middle ear, mastoid, and petrous bone. However, recurrent destructive tumor of the middle ear appeared after 26 months.Family historyThe family medical history disclosed the presence of symptoms of VHLD in the patient's grandfather, uncle, and father. In particular, the patient's father presented with multi-tumor syndrome and evidence of genetic VHLD due to causal mutation in VHL gene in exon 1 TCG(Ser65)→TTG(Leu). At the age of 30, he was operated on for cerebellar hemangioblastoma, and died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases 13 years later at the age of 43.

      PatientID: 1

      KindredID: 1

      Case: F, 25Y0M, Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: The family medical history disclosed the presence of symptoms of VHLD in the patient’s grandfather, uncle, and father. In particular, the patient’s father presented with multi-tumor syndrome and a confirmed genetic mutation of c.194C>T. The father died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases at the age of 43.

      CasePresentingHPOs: HP:0006880;HP:0030393 (cerebellar hemangioblastoma, endolymphatic sac tumour)

      CaseHPOFreeText: Woman presented with slowly progressive and gradual decrease in hearing (beginning at 24Y). At 23Y the patient had undergone brain surgery because of hemangioblastoma of the cerebellum. Physical examination revealed a middle ear mass that protruded into the external auditory canal (recurrent restrictive tumor)

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: genetic tests on tissue but suspected germline because father had same mutation, and 2 different tissue samples had same mutation; grandfather and uncle had VHL symptoms but not specified and no genetic confirmation

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    3. Most commonly, the tumors associated with VHLD include retinal, cerebellar, medullary, and spinal cord hemangioblastomas, renal cell carcinomas, and pheochromocytomas. The cell phenotype of these tumors varies according to the site; some tumors are epithelial, the others show an endocrine phenotype. Although most likely mesenchymal, the phenotype of hemangioblastomas has not been clearly defined yet. Histologically, most VHLD linked tumors share a number of features, including clear cell change, papillary cystic structures, and highly vascularized stroma. A possible explanation for the histological similarity between VHLD-associated tumors may lie in the abnormal function of the VHL gene. It is thought that the rich blood vessel supply in VHLD-related tumors may result from an abnormal or absent VHL-protein function, which may cause hypoxia-inducible factor (HIF) stimulation of angiogenesis. The VHL gene normally regulates vascular endothelial growth factor (VEGF), and there is evidence that inactivation of the VHL gene promotes VEGF overexpression and angiogenesis in VHL-associated tumors [12]. This link may explain the highly vascularized nature of all tumors associated with VHLD [1].The histopathological differential diagnosis of ELST includes middle ear adenoma, paraganglioma, chorioid plexus papilloma, and metastatic carcinoma of the thyroid, kidney, prostate, lung, and breast. Middle ear adenoma is a rare tumor displaying mucinous and neuroendocrine differentiation without formation of papillae. Adenomas form an avascular mass limited to the middle ear without bone destruction. Paragangliomas of the middle ear are cytologically benign and may demonstrate papillary structures and cuboidal cells with eosinophilic cytoplasm. However, paraganglioma cells are positive for chromogranin and synaptophysin, and at least focally they are arranged in characteristic nests. Chorioid plexus papilloma may be histologically similar to ELST, but it originates in the ventricle and does not invade bone. Currently, considerations of metastases from thyroid, breast, and prostate can be eliminated by immunohistochemistry. Positive staining for thyroglobulin, GCDFP-15 protein, estrogen and progesterone receptors, and prostatic-specific antigen, respectively, can help in this differential diagnosis. Differentiation of ELST from metastatic renal carcinoma can be more difficult, both tumors may occur in patients with VHLD, and immunohistochemistry does not help. Renal cell carcinoma, however, shows nuclear polymorphism and mitoses.ELST is a primary low-grade adenocarcinoma of the temporal bone that is presumed to originate from the vestibular endolymphatic system [5], [8]. An association of ELST and VHL disease was first published in a large study showing an increased prevalence of ELST among the patients with VHLD [18]. Subsequently, germline mutation of the VHL gene and somatic loss of the wild-type allele were demonstrated in ELST from VHL patients [13], [20]. Genetic analysis of the tumors in patients with VHLD supports the theory that an inherited mutation in one allele, followed by somatic loss of the other allele, is essential for development of the tumors. Tibbs et al. demonstrated a genetic mutation in the VHL gene within the ELST that was similar to mutations previously reported in other VHLD-associated tumors [19]. Somatic VHL gene mutations have been shown in sporadic cases of ELST [10], [21]. Hamazaki et al. [10] showed a mutation of the VHL tumor suppressor gene in a sporadic ELST in a patient without symptoms of VHL disease. Sequencing studies of tumor DNA disclosed a nucleotide substitution of G to T at position 546 of the VHL gene, resulting in an amino acid substitution (Tr to Cys, codon 117) [10]. In a previous analysis of four sporadic ELSTs, two of the cases showed a point mutation in the VHL gene [21]. In one case, Gly to Asp transversion was shown in exon 2, codon 114, whereas in the other case, a deletion in exon 1, codon 4 was identified. Two other sporadic cases of ELST did not show any mutation in the VHL gene [21]. Thus, the findings in this and previous studies warrant that the VHL gene is associated with ELST tumorigenesis when arising in the context of VHL disease. The role of VHL gene mutation in sporadic cases of ELST is still to be elucidated in future studies of additional cases.In conclusion, we have studied two cases of Heffner tumor of identical histomorphology and immunophenotype. One of the patients presented with a medical and family history of VHLD and proven inherited germline mutation of the VHL tumor suppressor gene. The latter was a sporadic case, in a patient with no symptoms of VHLD. While in the patient with VHLD, the ELST and cerebellar hemangioblastoma carry a mutation of VHL gene, resulting in C to T exchange at position 194, the consequence of which is an amino acid exchange S65L. No mutation of the VHL gene was found in all three exons analyzed and in exon–intron junctions in the sporadic case.
    1. The VHL germline mutation previously detected in the white blood cells of this patient was C407T, Ser65Leu. Mutation analysis of all the VHL exons revealed this germline mutation in exon 1 in all tumors analyzed; however, no additional somatic mutations were detected (Table 1)

      A 44-year-old man presented with a generalized epileptic attack. Diagnostic workup revealed a cystic left cerebellar tumor, which on histologic examination proved to be a hemangioblastoma. Identification of a VHL germline mutation (c.194C>T, reported as c.407C>T due to a difference in transcript sequence) in a blood sample of the patient confirmed the diagnosis. The patient also had retinal hemangioblastomas, and clear cell renal cell carcinoma around 51Y. Family history was positive for VHL disease, although no further information provided. The patient died 10 years later at 54Y from metastases to the heart and autopsy also confirmed pheochromocytoma and pancreatic endocrine tumour. Somatic and chromosomal imbalances in the tumours of this patient were also documented. ACMG PP4 phenotypes and family history consistent with VHL disease.

    1. Six major VHL-related lesions (CHB, RA, RCC, PCT, PHEO, and GS) were observed in the c.194C > T p.Ser65Leu mutational subgroup

      540 patients from 187 unrelated Chinese VHL families at the Peking University First Hospital were all screened for VHL clinical features and germline mutations. Of these, clinical characteristics were observed in 258 patients from 80 unrelated Chinese families. These were reported in this study, grouped by the 21 mutations found. PCR and MLPA on peripheral blood detected the VHL mutations. Possessing the p.S65L (c.194C>T) mutation, 24 members total from an unknown number of families were described, and phenotypic information was given for this group. With ages ranging from 15-65Y, hemangioblastomas were observed in 15/24 members, retinal capillary hemangioma in 2, renal cell carcinoma in 9, pancreatic cysts in 11, pheochromocytoma in 1, and a genital system tumor (epididymis or broad ligament) in 4 members. This cohort has been previously published in PMID 29330336; 28388566.

    1. detected point germline vhl mutations in 14 patients

      PatientID: 16

      KindredID: 16

      Case: 44Y0M, sex unknown, ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0005584; HP:0009711 (hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)

      CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    2. detected point germline vhl mutations in 14 patients

      PatientID: 6

      KindredID: 6

      Case: 35Y0M, sex unknown, ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0005584; HP:0009711 (hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)

      CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    3. detected point germline vhl mutations in 14 patients

      PatientID: 17

      KindredID: 17

      Case: 20Y0M, sex unknown, ethnicity unknown

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797; HP:0009711 (hemangioblastoma; retinal capillary hemangioma)

      CaseHPOFreeText: See Table 1&2 for retinal capillary hemangioma information

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 3404

      KindredID: 209

      Case: Sex Unknown, Age Unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CohortInfo: Families were recruited from the French VHL Registry. Enrolment in the study required identification of the germline VHL mutation (currently 85% of the families included in the French VHL Registry) and available data regarding renal phenotype. A total of 126 families fulfilled these criteria.

      CasePresentingHPOs: HP:0005584 (Renal cell carcinoma)

      CaseHPOFreeText: Moderate renal disease (less than five solid lesions requiring surgical treatment, either unilateral or bilateral). Individual RCC phenotype is noted as positive.

      CaseNotHPOs: N/A

      CaseHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: 9829912

      SupplementalData: Phenotype and genotype information can be found in Supplementary Table S1.

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    2. Molecular and clinical analysis of 126 French VHL families tested for renal involvement revealed 92 different mutations. 90 of these families had renal involvement. The p.S65L (c.194C>T) germline variant of the VHL gene was detected in an individual (ID 3404, Family 209). This patient presented with renal cell carcinoma. No family information is provided. This patient was previously published in PMID 9829912.

    1. KindredID:52

      GroupID: 6

      GroupSize: Unknown

      GroupNumberMales: Unknown

      GroupNumberFemales: Unknown

      GroupEthnicity: Unknown

      GroupAgeRange: Unknown

      DiseaseAssertion: VHL

      GroupInfo: Kindred no.52 describes a family where at least one member (unspecified how many) had this mutation in the VHL gene.

      GroupPresentingHPOs: N/A

      GroupHPOFreeText: N/A

      GroupNotHPOs: HP:0002666 (Pheochromocytoma)

      GroupNotHPOFreeText: Pheochromocytoma was not observed in any members of the affected patient(s)' family (VHL type 1).

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: c.407C>T (p.S136L)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence:

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    1. 194C>T65S65L

      A study of 34 Polish families revealed germline mutations in 30 families using DNA isolated from peripheral blood luykocytes to sequence through PCR and Quantitative Southern analysis. Mutations were not detected in 4 probands fulfilling clinical criteria for von Hippel-Lindau disease (VHLD). This missense mutation (c.194C>T) was found in a single VHL patient and 2 VHL families with multiple affected individuals. The patient had hemangioblastomas of the central nervous system (family no. 1). The VHL family of 4 affected individuals had one patient with retinal hemangioblastomas, 3 with hemangioblastomas of the central nervous system, and one with renal cell carcinoma (family no. 2). The VHL family of 12 individuals had 10 with retinal hemangioblastomas, 3 with renal cell carcinoma, and 12 with hemangioblastomas of the central nervous system (family no. 3). Supporting evidence of pathogenicity since there is cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (ACMG code: PP1).

  2. Nov 2026
    1. PatientID: V209

      KindredID: V209

      Case: Sex Unknown, Age Unknown, French

      DiseaseAssertion: VHL

      FamilyInfo: N/A

      CasePresentingHPOs: N/A

      CaseHPOFreeText: Diagnosed with VHL Type 1.

      CaseNotHPOs: HP:0002666 (Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. PatientID: 8

      KindredID: 5

      Case: M, 30Y0M, Chinese

      DiseaseAssertion: VHL

      FamilyInfo: The proband's grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease.

      CasePresentingHPOs: HP:0001737; HP:0001732; HP:0010797 (Pancreatic cysts, Abnormality of the pancreas, Hemangioblastoma)

      CaseHPOFreeText: The proband presented with a CNS hemangioblastoma at age 21 and a multiple pancreatic cysts/tumors at age 30.

      CaseNotHPOs: HP:0005584; HP:0009711; HP:0002666 (Renal cell carcinoma, Retinal capillary hemangioma, Pheochromocytoma)

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: This cohort was also published in a later paper by Wang et al., 2018 (PMID: 29330336).

      SupplementalData: Patient and family genotype-phenotype information is listed in Supplementary Table 1.

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975; https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L(c.194C>T)

      MultipleGeneVariants: N/A

    1. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected.

      GroupID/ KindredID: 52CA

      DiseaseAssertion: VHL

      GroupSize: N/A

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: This germline familial VHL mutation was taken from the Cambridge, Department of Pathology database, with an unknown number of members belonging to Family ID 52CA. Table 3 lists all ID and mutations associated with individuals possessing renal carcinoma, without phechromocytoma.

      GroupPresentingHPOs: HP:0005548 (renal cell carcinoma)

      GroupHPOFreeText: Described as a VHL familywith RCC, without pheochromocytoma. Other phenotypes are likely, however not detailed in this publication

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: N/A

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: p.S65L (c.407C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: N/A

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. Lung adenocarcinoma has never before been reported to be associated with von Hippel-Lindau (VHL) disease. Here, we report a case of VHL disease in a patient who had metachronous multiple lung adenocarcinomas. The patient is a 64-year-old-woman with VHL disease. She underwent surgical resection of one adenocarcinoma and one atypical adenomatous hyperplasia. A second lung adenocarcinoma developed metachronously. A point mutation in the VHL gene was confirmed in DNA from a blood sample, and loss of heterozygosity at the VHL locus was detected in the lung adenocarcinoma. The VHL dysfunction may have a role in the development of multiple lung adenocarcinomas.

      PatientID: 1

      KindredID: 1

      Case: F, 64Y0M, Japanese

      DiseaseAssertion: VHL

      FamilyInfo: Her father was killed in an accident when she was young. Her older brother died of renal cell carcinoma associated with VHL disease at the age of 58. Her younger sister was also diagnosed with renal cell carcinoma that was associated with VHL disease. No members past the proband had been genetically tested.

      CasePresentingHPOs: HP:0006880; HP:0030078; HP:0005584; HP:0001737 (cerebellar hemangioblastoma; lung adenocarcinoma; renal cell carcinoma; pancreatic cysts)

      CaseHPOFreeText: of a hemangioblastoma of the cerebellum when she was 37 years old. Her right kidney was resected because of renal cell carcinoma at the age of 59. Concurrently, she received a pancreatojejunostomy for a pancreatic cyst. At the age of 63, radiofrequency ablation was performed for renal cell carcinoma of her left kidney. In the same year, computed tomography screening of the patient’s lungs detected nodules in the right middle lobe and left upper division. A computed tomography–guided needle biopsy of the nodule in the right middle lobe resulted in a diagnosis of adenocarcinoma (Fig 1). We concurrently performed a lobectomy of the patient’s right middle lobe and a partial resection of the left upper division.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: Loss of heterozygosity (LOH) at the VHL locus was detected in the lung adenocarcinoma. The hepatic adenocarcinoma was found with somatic EGFR mutations and loss of heterozygosity at the VHL locus; authors speculate that dysfunctional pVHL may promote mutations on the EGFR gene.

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. nt 407 C/T 65 Ser→Leu S65L Missense 1

      PatientID: 1

      GroupID/ KindredID: 1

      Case: Sex Unknown, Age Unknown, Ethnicity Unknown

      DiseaseAssertion: hemangioblastoma

      FamilyInfo: N/A

      CasePresentingHPOs: HP:0010797 (hemangioblastoma)

      CaseHPOFreeText: other phenotypes unknown

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: p.S65L (c.407C>T)

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant; transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

  3. Oct 2026
    1. GroupID: 52

      DiseaseAssertion: assumed VHL

      GroupSize: 11

      GroupNumberMales: N/A

      GroupNumberFemales: N/A

      GroupEthnicity: N/A

      GroupAgeRange: N/A

      GroupInfo: 11 of the 573 patients discussed in this paper were found to have identical variants. This mutation (c.194C>T) was found in 4 VHL families with 11 patients altogether.

      GroupPresentingHPOs: HP:0006880; HP:0005584; HP:0009711 (cerebellar hemangioblastoma; renal cell carcinoma; retinal capillary hemangioma)

      GroupHPOFreeText: 4 total patients had cerebellar hemangioblastoma; 2 had renal cell carcinoma; and 10 patients had retinal capillary hemangioma. Mean ages for each diagnosis follows: 25Y (RH), 43Y (CHB), 48Y (RCC).

      GroupNotHPOs: HP:0002666 (pheochromocytoma)

      GroupNotHPOFreeText: No patients had pheos

      GroupPreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: Supplementary Table S1.

      Variant: p.S65L (c.194C>T)

      CaseProblemVariantFreeText: N/A

      LegacyVariant: N/A

      ClinVarID: 182975 https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. nt 407 C/T 65 Ser→Leu S65L Missense

      A cohort of 141 patients with hemangioblastomas of the central nervous system was analyzed. 81 patients had germline mutations in the VHL gene, analyzed through peripheral blood by Southern blotting and SSCP analysis. This missense mutation (c.194C>T) was recorded in the paper as c.407C>T due to a difference in transcript sequence. It was found in one patient with hemangioblastomas of the central nervous system. No other phenotype described.

    1. Family historyThe family medical history disclosed the presence of symptoms of VHLD in the patient's grandfather, uncle, and father. In particular, the patient's father presented with multi-tumor syndrome and evidence of genetic VHLD due to causal mutation in VHL gene in exon 1 TCG(Ser65)→TTG(Leu). At the age of 30, he was operated on for cerebellar hemangioblastoma, and died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases 13 years later at the age of 43.

      PatientID: N/A (father)

      KindredID: 1

      Case: M, 43Y0M (deceased), Ethnicity Unknown

      DiseaseAssertion: assumed VHL

      FamilyInfo: The family medical history disclosed the presence of symptoms of VHLD in the patient’s daughter, brother, and father. His daughter was detected with the c.194C>T mutation in two of her tumors, likely germline with the familial relations. She also had undergone brain surgery at 23Y due to a cerebellar hemangioblastoma, and an ELST

      CasePresentingHPOs: HP:0006880; HP:0005584 (cerebellar hemangioblastoma; Renal cell carcinoma)

      CaseHPOFreeText: At the age of 30, he was operated on for cerebellar hemangioblastoma, and died of disseminated bilateral renal cell carcinoma of kidneys with multi-organ distant metastases 13 years later at the age of 43.

      CaseNotHPOs: N/A

      CaseNotHPOFreeText: N/A

      CasePreviousTesting: N/A

      PreviouslyPublished: N/A

      SupplementalData: N/A

      Variant: p.S65L (c.194C>T)

      LegacyVariant: N/A

      CaseProblemVariantFreeText: N/A

      ClinVarID: 182975, https://www.ncbi.nlm.nih.gov/clinvar/variation/182975/

      CAID: N/A

      gnomAD: https://gnomad.broadinstitute.org/variant/3-10183725-C-T

      VariantEvidence: N/A

      MutationType: missense_variant;transition

      CivicName: S65L (c.194C>T)

      MultipleGeneVariants: N/A

    1. A retrospective cohort study included all the VHL patients diagnosed at Peking University First Hospital (Beijing, China) prior to June 1 2016. A total of 291 patients from 115 different families were included for analysis. Genotyping confirmation was performed by PCR-direct sequencing on peripheral blood samples. This mutation was confirmed in families #4, #5, and #5. Only the proband of family #4 (male, patient #7) was genetically confirmed with the mutation. He was diagnosed with renal cell carcinoma and multiple pancreatic cysts/tumors at age 33. Only the proband of family #5 was genetically confirmed with the mutation. He presented with a CNS hemangioblastoma at age 21 and multiple pancreatic cysts and tumors at age 30. His grandfather, father, and uncle presented with a CNS hemangioblastoma at ages 30, 36, and 33, respectively, and all passed away before they could be diagnosed with VHL disease. Family #6 is large: the proband (F, renal cell carcinoma at age 36 and pheochromocytoma at age 37) had 8 family members genetically confirmed with the mutation and two family members who passed away before diagnosis. The 8 genetically confirmed family members include patient 13 (asymptomatic,) 14 (CNS hemangioblastoma at age 59,) 15 (CNS hemangioblastoma age 45, renal cell carcinoma at 59, multiple pancreatic cysts/tumors at 65), 18 (CNS hemangioblastoma at age 22, renal cell carcinoma at 30, multiple pancreatic cysts/tumors at 31,) 19 (asymptomatic), 20 (asymptomatic), 21 (CNS hemangioblastoma and retinal angioma at 53,) and 22 (multiple pancreatic cysts/tumors at 29). The 2 family members who passed away before diagnosis are patients 16 (CNS hemangioblastoma at 22) and 17 (CNS hemangioblastoma, renal cell carcinoma, and multiple pancreatic cysts/tumors at age 51). This cohort was also published in a paper by Wang et al., 2018 (PMID: 29330336).

    1. The VHL gene product (pVHL) has two macromolecular sites, α and β domains, which can bind different proteins. pVHL bound to elongin B, C/cullin/Rbx1 acts as an E3 ubiquitin ligase and targets proteins for degradation.22 Similarly, hypoxia inducible proteins are regulated by complex pVHL/elongin B and C that requires direct binding of hypoxia inducible factor (HIF) to the β domain and targets HIF for ubiquitination catalysed by the α domain.23 The VHL protein also plays a role in extracellular matrix formation and is necessary for cell cycle exit.24,25 Germline VHL mutations cause different protein defects that result in the clinical heterogeneity of VHL disease. VHL type 1 disease (without phaeochromocytoma) is associated with mutations predicted to cause complete unravelling of protein structure (missense mutations mapping to VHL protein hydrophobic core, protein truncating mutations, and partial gene deletions). VHL type 2 (with phaeochromocytoma) is caused by missense mutations which map to protein binding sites of pVHL and are predicted to cause local protein defects.22 Specific phaeochromocytoma associated missense mutations confer different risks of HAB and RCC, being responsible for the occurrence of subcategories VHL type 2A (VHL without RCC), 2B (VHL with RCC), and 2C (phaeochromocytoma only).15 Phenotypic expression of VHL disease is also influenced by genetic modifiers.26